He made his film debut in director Martin Scorsese's thesis project, Who's That Knocking at My Door? (1968). Keitel's association with Scorsese continued, providing some of his most memorable roles in Mean Streets, Alice Doesn't Live Here Anymore, Taxi Driver and The Last Temptation of Christ.
His performance as gangster Mickey Cohen in Bugsy earned him a Best Supporting Actor Oscar nomination in 1992. Adding to his cult mystique were his appearances in From Dusk Till Dawn and Quentin Tarantino's Reservoir Dogs and Pulp Fiction.